pantetheine and Alzheimer-Disease

The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-β (Aβ)-induced IL-1β release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer's disease (AD).1.5-month-old Tg and wild-type (WT) male mice were submitted to intraperitoneal administration of pantethine or saline control solution for 5.5 months. The effects of such treatments were investigated by performing behavioral tests and evaluating astrogliosis, microgliosis, Αβ deposition, and whole genome expression arrays, using RNAs extracted from the mice hippocampi. We observed that long-term pantethine treatment significantly reduced glial reactivity and Αβ deposition, and abrogated behavioral alteration in Tg mice. Moreover, the transcriptomic profiles revealed that after pantethine treatment, the expression of genes differentially expressed in Tg mice, and in particular those known to be related to AD, were significantly alleviated. Most of the genes overexpressed in Tg compared to WT were involved in inflammation, complement activation, and phagocytosis and were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of Αβ processing and synaptic activities, which were downregulated in Tg mice. Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by Aβ pathogenesis in Tg mice and highlight the potential efficiency of pantethine to alleviate AD pathology.

Topics: Aggression; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Humans; Male; Mice; Mice, Transgenic; Pantetheine; Phagocytosis; Time Factors

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Astrocytes; Cell Survival; Cells, Cultured; Citric Acid Cycle; Disease Models, Animal; Gene Expression; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-1beta; Metabolomics; Mice; Mice, Transgenic; Pantetheine; Pentose Phosphate Pathway; Presenilin-1; RNA, Messenger